Most life stress literature in bipolar disorder (BD) fails to account for the possibility of a changing relationship between psychosocial context and episode initiation across the course of the disorder. The kindling hypothesis states that over the longitudinal course of recurrent affective disorders, there is a weakening temporal relationship between major life stress and episode initiation (Post, 1992). This process could reflect either a progressive sensitization or a progressive autonomy (i.e., insensitivity) to life stress. The present study aimed to test the kindling model in BD by examining the effect of lifetime mood episodes on the relationship between proximal life events and prospectively assessed mood episodes. Polarity-specific tests of the model were conducted across the continuum of event severity, with respect to both impact and frequency of life events. Moreover, examination of the kindling hypothesis was embedded in the context of two emerging biopsychosocial theories of BD: the expanded Behavioral Approach System Dysregulation Model and the Circadian and Social Rhythm Theory. Data from 278 participants (146 bipolar spectrum participants and 132 normal control participants) were collected as part of the Temple-Wisconsin Longitudinal Investigation of Bipolar Spectrum Project. Hypotheses were polarity- and event-type specific and were in line with a stress sensitization model of bipolar spectrum disorders (BSD), rather than a stress autonomy model. Results partially supported a sensitization model: there was a decreased frequency and an increased impact of major events, and an increased frequency and impact of minor events. However, results for specific polarities and event types were not fully consistent with a stress sensitization model. Implications of these findings are addressed, followed by a discussion of study strengths, limitations, and promising directions for future research. / Psychology

In this study, I tested predictions of the Behavioral Approach System (BAS) model as applied to the course of bipolar spectrum disorders. In this model, when a vulnerable individual experiences a BAS activation-relevant event, the weak regulatory strength of the BAS interacts with pre-event BAS state and is likely to lead to hypomania/mania. In contrast, when a vulnerable individual experiences a BAS deactivation-relevant event, the weak regulatory strength of the BAS interacts with pre- event BAS state and is likely to lead to depression. A secondary goal of this study involved comparing the BAS model to the cognitive-vulnerability stress model of bipolar disorder. Toward this end, data from a sample of 217 individuals (112 individuals with a diagnosis in the bipolar spectrum and 105 demographically similar, normal controls) participating in the Longitudinal Investigation of Bipolar Spectrum Disorders (LIBS) Project, a two-site prospective examination of the role of BAS, cognitive styles, and life events in the course of bipolar disorders among college students, were analyzed. The results of this study suggest that there is some support for both the BAS model and the cognitive-vulnerability stress model. Specifically, BAS-relevant cognitive styles, in interaction with congruent positive life events, predicted hypomanic episodes. There was less support for either model in the prediction of depression. There was some support for BAS sensitivity and BAS-relevant events each predicting the course of bipolar disorder. However, there was no support for the interaction of BAS sensitivity and BAS-relevant events predicting the type and number of mood episodes. As such, this study found more support for a BAS-related cognitive vulnerability-stress model, as compared to the "pure" BAS model, as applied to bipolar spectrum disorders. Following a review of the results, strengths and limitations, as well as clinical implications and potential future research directions are discussed. / Psychology

Bipolar disorder (BD) is a chronic mood disorder affecting ~1-2% of the global population, characterized by cycling moods of mania and depression. The exact pathogenesis of BD is unknown; however, it has been established that endoplasmic reticulum (ER) stress plays an important role. It is known that BD patients have abnormal activity and expression of ER stress proteins in several brain regions. There exists a need for a definitive diagnostic test for the early detection of BD as it is often misdiagnosed for other conditions including unipolar depression and schizophrenia. Understanding the underlying mechanisms and therapeutic targets being used by BD treatments will be helpful in establishing a diagnostic test. The current gold standard for BD treatment includes Lithium (LiCl) prescription, along with other mood stabilizers such as Valproic acid (VPA) and antipsychotics such as Olanzapine. Current therapies only relieve symptoms and are unable to stop disease progression. Neurotrophic factors (NTFs) are naturally occurring proteins that are responsible for the maintenance, differentiation, and survival of neurons. Cerebral dopamine NTF (CDNF) and Mesencephalic astrocyte-derived NTF (MANF) belong to a novel class of NTFs specific to dopaminergic neurons. This study investigated the role of CDNF and MANF as therapeutic targets for bipolar disorder in SH-SY5Y cells and Sprague Dawley rats, as well as determining the endogenous mRNA levels of CDNF and MANF in BD patients. We demonstrated that common BD mood stabilizers – LiCl and VPA – significantly increased the mRNA expression of MANF and CDNF in vitro. Additionally, we also established that these mood stabilizers alter the NTFs expression in different rat brain regions including pre-frontal cortex (PFC) and cortex. These findings suggest that BD drug treatments potentially act via NTFs in order to relieve symptoms. Thus it highlights the importance of further investigating the interaction between neurotrophic factors and bipolar disorder. / Thesis / Master of Science (MSc)

The aetiology of bipolar disorder remains unclear and investigation to date has focussed largely on bipolar patients. Whilst ultimately of huge value, such studies may also be confounded by current mood or experience of repeated illness episodes or current or past medication; using at-risk samples may bypass some of these problems. The current research therefore assessed the efficacy of the Mood Disorder Questionnaire (MDQ) as a screening tool for vulnerability to bipolar disorder. The MDQ was used with two sets of criteria to identify two sub-groups of medication-naïve young bipolar phenotype subjects who were at risk for bipolar disorder by virtue of experience of mood elevation. Analysis of data from the Student Stress Survey was carried out to characterise the bipolar phenotype. Compared to a control group with no experience of mood elevation, the two bipolar phenotype sub-groups showed a gradient of prevalence of bipolar diagnosis and associated co-morbidity. Behavioural and functional magnetic resonance imaging (fMRI) techniques were employed to investigate emotional processing, decision-making, and sleep and circadian rhythmicity in bipolar phenotype students. Analyses revealed that positive emotional processing biases, disrupted decision-making, and increased activity during sleep were associated with the bipolar phenotype and, therefore, may represent vulnerability markers for bipolar disorder. Finally, a psychopharmacological investigation of quetiapine, which stabilises mood, was carried out in healthy volunteers. One-week quetiapine administration resulted in biases away from both positive and negative emotional stimuli (i.e. a mood-stabilising effect), reduced discrimination between different magnitudes of gains and losses during risky decision-making (consistent with an antidepressant effect), and increased sleep duration. In sum, this research has developed our understanding of vulnerability markers associated with the bipolar phenotype and provided a first step towards uncovering the psychological mechanisms through which quetiapine’s clinical effects may be mediated.

Text in English / Literature notes an increase in the number of children and adolescents diagnosed with bipolar disorder. Several challenges faced by clinicians who diagnose and treat early-onset bipolar disorder have been discussed with particular emphasis being placed on its pharmacological management. The contributions made by psychologists including psychosocial interventions, have been explored in this regard; however, there still exists a paucity of voices in the field of psychology that discuss the experiences surrounding the management of this disorder. Most studies on early-onset bipolar disorder do not distinguish between childhood and adolescent presentations. Adolescence has been recognized herein, as a distinct developmental and transitional phase and thus, it forms the basis of this inquiry. This qualitative study thus explores clinical psychologists’ experiences ofmanaging adolescents diagnosed with bipolar disorder and will be approached from a social constructionist perspective which was selected as a means of exploring the meanings that individuals attribute to their experiences as they engage with others in their environment. A literature review evaluated the current available literature on juvenile bipolar disorder. Clinical psychologists in private practices were interviewed using semi-structured interviews. The participants were selected using purposive sampling. Two pilot studies were used to pre-test the study. One participant took part in pilot study 1 and one in pilot study 2. Thereafter, four semi-structured interviews were held with four participants who took part in the main study. Themes were drawn from the data and were explored using thematic content analysis. An analysis of the themes revealed several shared experiences in clinical psychologists’ management of juvenile bipolar disorder which were similar to what is reflected in the current available literature on early-onset bipolar disorder. / Psychology / M.A. (Clinical Psychology)

O HCL-32 é um questionário de 32 itens, de auto-aplicação, onde os sintomas são avaliados através de respostas do tipo \"sim\" (presente ou típico) ou \"não\" (não está presente ou atípico). Além disso, o HCL-32 tem 8 seções para avaliar a gravidade e o impacto dos sintomas sobre os diferentes aspectos da vida do paciente. A pontuação é obtida pela soma das respostas positivas para os 32 itens sobre hipomania. A versão original do HCL-32 foi traduzido e adaptado para o português brasileiro. A primeira versão do HCL-32 foi traduzida por nós, revisados por especialistas em transtornos de humor, bem como por um professor de português brasileiro. Foi então retro-traduzida por um professor de inglês americano. Dos indivíduos inicialmente selecionados, foram excluídos 27, 11 devido à presença de comorbidades com abuso de substância, e 16 devido à incapacidade de preencher corretamente o questionário. Assim, nossa amostra final ficou composta por 81 pacientes com TB (37 TBI; 44TBII), 42 com TDM, e 362 sujeitos de uma população não clínica. A consistência interna foi elevada, com um alfa de Cronbach de 0,793 para todo o HCL-32 VB, indicando que os itens do questionário são suficientemente homogêneos. Indivíduos com TB tiveram a maior pontuação no HCL-32 VB. A média de respostas afirmativas foi significativamente diferente de acordo com o diagnóstico. Analisamos a capacidade em diferenciar os diagnósticos através da curva ROC. A área sob a curva foi de 0.702, indicando a boa capacidade da escala para distinguir entre diagnósticos. A melhor combinação de sensibilidade (0.75) e especificidade (0.58) ocorreu com uma pontuação acima de 18. Esta pontuação distinguiu entre pacientes com TB e TDM. Para comparar as propriedades discriminativas do HCL-32 VB e MDQ VB, foram calculadas a sensibilidade e especificidade de ambos os questionários. A HCL-32 VB teve uma sensibilidade de 0.75 e especificidade de 0.58. O MDQ teve sensibilidade de 0.70 e especificidade de 0.58. Assim, a HCL-32 BV apresentou maior sensibilidade, mas a mesma especificidade que o MDQ. A análise fatorial resultou em nove fatores com autovalores > 1, explicando 53,1% da variância total. De acordo com o teste Scree, foi preferida uma solução com três fatores. O primeiro fator, com autovalor de 4,90, explicou 15,3% da variância e foi composto por 10 itens. Essa subescala reflete questões relacionadas com ativação/elação. O segundo fator, com autovalor de 3,48 (10,88% da variância), composto por 11 itens e sua estrutura inclui questões relacionadas com \"irritabilidade / comportamento de risco\". O terceiro fator, com autovalor de 1,56 (4,87% da variância), ficou composto por cinco itens e sua estrutura reflete questões relacionadas com \"desinibição / ativação sexual. Os parâmetros psicométricos de HCL-32 VB sugerem que é um instrumento útil para a detecção de hipomania em pacientes com transtornos de humor. O HCL-32 VB é um questionário rápido de auto-aplicação e de fácil interpretação / The HCL-32 is a 32-item self-administered questionnaire where symptoms are assessed through yes (present or typical) or no (not present or untypical) answers. In addition, the HCL-32 has 8 other sections evaluating the severity and impact of the symptoms on different aspects of patient\'s life. The score is obtained by adding the positive responses to the 32 symptoms of hypomania. The original version of the HCL-32 was translated and adapted to Brazilian Portuguese .The first draft of the Brazilian version was translated by us, reviewed by experts in mood disorders, as well as by a Brazilian-Portuguese teacher. It was then back-translated by an English (American) teacher. Of the individuals initially enrolled, 27 individuals were excluded; 11 due to the presence of comorbidities with substance abuse, and 16 due to inability to properly fill the questionnaires. Accordingly, our final sample comprised of 81 patients with BP (37 BPI; 44 BPII), 42 with MDD, and 362 subjects from a nonclinical population. Internal consistency was high, with a Cronbach\'s alpha of 0.793 for the entire HCL-32 BV, indicating that the items of the questionnaire are sufficiently homogeneous. Individuals with BP had the highest HCL-32 BV scores. The mean number of affirmative responses to the list of symptoms was significantly different according to diagnosis. We analyzed the scale\'s discrimination for BP trough the ROC curve. The area under the curve was 0.702 indicating the good ability of this screening scale. The best combination of sensitivity (0.75) and specificity (0.58) happened with a score above 18. This score discriminates between BP patients and MDD. To compare the discriminative properties of HCL-32 BV and MDQ, we calculated the sensitivity and specificity of both questionnaires. The HCL-32 BV had a sensitivity of 0.75 and specificity of 0.58. The MDQ had sensitivity of 0.70 and specificity of 0.58. Hence, the HCL-32 BV showed higher sensitivity but the same specificity than the MDQ. The factor analysis resulted in 9 factors with eigenvalues > 1, explaining 53.1% of the total variance. According to the Scree test, a 3-factor solution was preferred. The first factor, with an Eigenvalue of 4.90, explained 15.3% of the variance and comprised 10 items . This subscales structure reflects questions related to active/elated symptoms. The second factor, with an Eigenvalue of 3.48 (10.88% of the variance), comprised 11 items and its structure includes questions associated with irritable/risk-taking items. The third factor, with an Eigenvalue of 1.56 (4.87% of variance), comprised 5 itens and its structure reflect questions related to disinhibition/activation sexual. The psychometric parameters of HCL-32 BV suggest it as a useful instrument for the detection of hypomania in patients with mood disorders. HCL-32 BV is a brief, self-administered questionnaire of easy application and interpretation

Huvudsyftet med denna uppsats är att analysera hur människor med bipolär sjukdom upplever att deras sjukdom påverkar deras livkvalitet. Vårt andra syfte är att analysera hur hur människor med bipolär sjukdom upplever insatserna de mottagit från socialtjänsten och Försäkringskassan. Uppsatsen har genomförts utifrån att vi analyserat tre olika självbiografier, Cecilia Asps bok Med mitt liv i mina händer - att leva med bipolär sjukdom, Carrå med Å´s bok Det stavas bipolär och kanske en gnutta borderline och Jenny Sandfors bok Bipolär fånge i min egna historia. Med hjälp av dessa självbiografier har vi insamlat material för att kunna besvara våra frågeställningar. De teorier vi valt att använda oss av i denna uppsats är Erving Goffmans teori avseende stigma, KASAM som är en sociologisk teori utformad av Aaron Antonovsky och empowerment. Goffmans teori går kortfattat ut på att stigma skapas ur situationer där individer upplever att de inte kan bemöta de krav och förväntningar som samhället har på dem. Antonovskys teori används i syftet att se vilka oordningar som författarna upplever samt vilka medel de funnit som kan användas som ett motstånd mot dem och på så sätt visa hur de hanterade livskriser som bipolär sjukdom kan ha gett författarna. Empowerment utgår från att delad makt inte minskar en annans makt och genom samverkan och samarbete så går det att dela kunskap och makt genom råd och stöd. Med utgångspunkt i empowerment undersöks hur författarna upplever mötet med myndigheter som socialtjänsten och Försäkringskassan. Med hjälp av teorierna kommer vi fram till att det finns likheter mellan Sandfors, Carrå med Å och Asps upplevelser av sin bipolära sjukdom, men också att det finns skiljaktigheter som visar på att sjukdomen påverkar människor på olika sätt. / The main purpose of this study was to analyze how people with bipolar disorder's quality of life is affected by the disorder. Our secondary purpose was to analyze how individuals with bipolar disorder experience the contributions of social workers and Försäkringskassan. The essay was carried out based on three different autobiographies that we analyzed; Cecilia Asps book "Med mitt liv i mina händer - att leva med bipolär sjukdom", Carrå med Å's book "Det stavas bipolär och kanske en gnutta borderline" and Jenny Sandfors book "Bipolär fånge i min egna historia", from which we collected material in order to be able to answer the question at hand. The theories of choice for the thesis has been; Erving Goffman's theory on stigma. KASAM a social theory authored by Aaron Antonovsky and empowerment. Goffman's theory covers the stigma that was created from situations where individuals feel that they cannot meet the demands and expectations society has of them. Antonovsky's theory was used for the purpose of studying which obstacles that the study participants experience and what means they have discovered to handle those obstacles. Empowerment assumes that shared power does not diminish individual power, and through collaboration and cooperation creates the possibility to share knowledge and power through advice and support. By using the aforementioned theories we found similarities between the three different authors of the autobiographies, but also differences in their personal experiences dealing with bipolar disorder.

This study applies statistical models to mood in patients with bipolar disorder. Three analyses of telemonitored mood data are reported, each corresponding to a journal paper by the author. The first analysis reveals that patients whose sleep varies in quality tend to return mood ratings more sporadically than those with less variable sleep quality. The second analysis finds that forecasting depression with weekly data is not feasible using weekly mood ratings. A third analysis shows that depression time series cannot be distinguished from their linear surrogates, and that nonlinear forecasting methods are no more accurate than linear methods in forecasting mood. An additional contribution is the development of a new k-nearest neighbour forecasting algorithm which is evaluated on the mood data and other time series. Further work is proposed on more frequently sampled data and on system identification. Finally, it is suggested that observational data should be combined with models of brain function, and that more work is needed on theoretical explanations for mental illnesses.

Bipolar disorder is a heritable psychiatric disorder, and several of the genes associated with bipolar disorder and related psychotic disorders are involved in the development and maintenance of white matter in the brain. Patients with bipolar disorder have an increased incidence of white matter hyper-intensities, and quantitative brain imaging studies collectively indicate subtle decreases in white matter density and integrity in bipolar patients. This suggests that genetic vulnerability to psychosis may manifest itself as reduced white matter integrity, and that white matter integrity is an endophenotype of bipolar disorder. This thesis comprises a series of studies designed to test the role of white matter in genetic risk to bipolar disorder by analysis of diffusion tensor imaging (DTI) data in the Bipolar Family Study. Various established analysis methods for DTI, including whole-brain voxel-based statistics, tract-based spatial statistics (TBSS) and probabilistic neighbourhood tractography, were applied with fractional anisotropy (FA) as the outcome measure. Widespread but subtle white matter integrity reductions were found in unaffected relatives of patients with bipolar disorder, whilst more localised reductions were associated with cyclothymic temperament. Next, the relation of white matter to four of the most prominent psychosis candidate genes, NRG1, ErbB4, DISC1 and ZNF804A, was investigated. A core haplotype in NRG1, and three of the four key single nucleotide polymorphisms (SNPs) within it, showed an association with FA in the anterior thalamic radiations and the uncinate fasciculi. For the three SNPs considered in ErbB4, results were inconclusive, but this was consistent with the background literature. Most notable however, was a clear association of a non-synonymous DISC1 SNP, Ser704Cys, with FA extending over most of the white matter in the TBSS and voxel-based analyses. Finally, FA was not associated with a genome-wide supported risk SNP in ZNF804A, a finding which could not be attributed to a lack of statistical power, and which contradicts a strong, but previously untested hypothesis. Whilst the above results need corroboration from independent studies, other studies are needed to address the cellular and molecular basis of these findings. Overall, this work provides strong support for the role of white matter integrity in genetic vulnerability to bipolar disorder and the wider psychosis spectrum and encourages its future use as an endophenotype.

Although psychological research into manic experiences is increasing, it remains an underresearched phenomenon. In particular, there is a dearth of qualitative research exploring these experiences in a clinical sample of people diagnosed with Bipolar Disorder. This study examined six participants’ experiences of mania using Interpretative Phenomenological Analysis. Through semi-structured interviews, the participants provided detailed accounts of how they made sense of and experienced their manic states. Three master themes were described: “A mixed relationship with mania,” “A separate and controlled self”, and “The struggle to be different.” The first master theme explored the participants’ mixed and ambivalent relationship with their manic experiences. These were viewed as both alluring and dangerous, but overall the perceived costs had outweighed the benefits, for all but one of the participants. Most participants described losses in relation to giving up their manic experiences, as well as losses related to the destructive consequences of their episodes. The second master theme examined perceptions of mania as a separate, uncontrollable phenomenon, over which they had little influence. It was hypothesised that these explanations served to relieve these participants from underlying negative emotions, such as guilt, regret, shame and selfstigma. The third master theme described how manic experiences had represented struggles to be different. These included a struggle against society; a struggle to experience a preferred self; and a struggle to access very unique experiences or abilities. A number of issues were discussed in relation to the above themes. These included positive and conflicting appraisals of high moods; loss; entrapment and helplessness; ambivalence; negative moral emotions and a preferred manic identity. A range of therapeutic approaches were suggested as potentially helpful for some of these issues. These included Motivational Interviewing, Narrative, Constructivist and Compassion therapies. Additionally, the findings of the study provided support for existing therapies for Bipolar Disorder; particularly Cognitive-Behavioural Therapy (CBT) and Interpersonal & Social Rhythm Therapy (IPSRT).